ABSTRACT Epidermis and its appendages constitute the outermost skin barrier essential for mammalian health and survival. Dysregulation of cell signaling in epidermal cells involving NF-?B, AP1, and c-Myc gene regulators can lead to local and systemic disorders, as well as cancer. Nevertheless, direct targeting of these core transcription factors has been proven technically challenging, prohibiting a meaningful clinical translation. Our long-term objective is to explore how K63-Ubiquitin (K63-Ub)-mediated signals converge on gene regulation and can be rationally targeted for therapy of inflammatory and neoplastic skin disorders. Towards this end, our recent efforts are focused on characterizing novel functions of CYLD, a K63-Ub protease whose loss-of- function is linked to immunological diseases, infertility, and benign and malignant neoplasms. While mutant Cyld in humans leads to Cyldm-syndrome characterized by widespread and recurrent epidermal and appendage tumors, understanding the complete role of CYLD is hampered by the lack of a clinically relevant disease model. To uncover novel disease mechanisms we have generated a mouse model that recapitulates genetic and phenotypic features of human Cyldm-syndrome. Using this animal model, we have identified c-Myc as a new CYLD substrate, UBE2N as an upstream regulator of c-Myc and androgen signaling, in addition to a role of CYLD in the regulation of the NF-?B and AP1 pathways. These findings highlight the broad impact of CYLD and the utility of the Cyldm skin model for increasing our understanding of novel disease mechanisms. This study is designed based on the hypothesis that unopposed UBE2N function in epithelial cells promotes inflammation and c-Myc-dependent skin defects. We propose three specific aims: 1) to define the role of c-Myc in Cyldm skin; 2) to determine the molecular mechanisms underlying K63-Ub-mediated c-Myc activation; and 3) to determine the functions of UBE2N in epidermal proliferation and tumorigenesis. We will utilize mouse and human skin tissue models, as well as cutting-edge technologies for gene editing, transcriptome and protein interactome analyses. Completion of these studies will reveal novel molecular mechanisms of epidermal morphogenesis and provide therapeutic insights for skin inflammation and cancer.